LAUSR

Bleeding correlates with disease severity in viral hemorrhagic fevers. We found that the increase in type I interferon (IFN-I) in mice caused by infection with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV; an arenavirus) reduced the megakaryocytic expression of genes encoding enzymes involved in lipid biosynthesis (cyclooxygenase 1 and thromboxane A synthase 1) and a thrombopoietic transcription factor (Nf-e2). The decreased expression of these genes was associated with reduced numbers of circulating platelets and defects in the arachidonic acid synthetic pathway, thereby suppressing serotonin release from δ-granules in platelets. Bleeding resulted when severe thrombocytopenia and altered platelet function reduced the amount of platelet-derived serotonin below a critical threshold. Bleeding was facilitated by the absence of the activity of the kinase Lyn or the administration of aspirin, an inhibitor of arachidonic acid synthesis. Mouse platelets were not directly affected by IFN-I because they lack the receptor for the cytokine (IFNAR1), suggesting that transfusion of normal platelets into LCMV-infected mice could increase the amount of platelet-released serotonin and help to control hemorrhage. Description Defective platelets generated from megakaryocytes exposed to arenaviral infection–induced interferon increase bleeding risk. From bone marrow to hemorrhage Infections with some viruses, including arenaviruses, can cause hemorrhage that can be fatal. Aiolfi et al. found that bleeding from arenaviral infection in mice resulted from interferon-α produced during infection inducing the formation of defective platelets through a pathway that did not act directly on platelets, which lack interferon receptors. Instead, interferon-α decreased the expression of genes involved in platelet formation and function in megakaryocytes, bone marrow cells that generate platelets. Infected mice produced fewer platelets that were less functional, such as releasing less serotonin, an effect that would be expected to increase bleeding. Thus, megakaryocytes are the targets of interferon-α in the bone marrow and transfer gene expression reprogramming to the platelets that they generate.